To identify chromosomal regions containing susceptibility genes for NIDDM, we have undertaken an autosomal genome-scan for DNA markers linked to pre-diabetic metabolic phenotypes in non-diabetic Pima Indians. 363 Pimas from 109 nuclear families (comprising 388 sib-pairs) were genotyped with 517 microsatellite DNA markers. Sib-pair linkage analysis identified 5 markers (D4S1627-D4S3242-D4S3241-D4S3255-D4S3248) within a 12 cm region on chromosome 4 which are potentially linked to the glucose response to a 75g oral glucose tolerance test (p<0.04), a mixed meal (p<0.003), or an intravenous glucose bolus (p<0.006) after adjusting for age, sex and obesity. The Gc locus, which encodes the vitamin D binding protein, maps to this region on 4q12. Since this locus has previously been associated with NIDDM in southwest Pacific Island populations, and has been associated with fasting plasma insulin and glucose levels in Dogrib Indians of the Northwest Territories, and fasting plasma glucose levels in a Hispanic-Anglo U.S. population, we analyzed this locus as a candidate gene for our linkage findings in Pimas. We sequenced all 12 exons of this gene and identified two polymorphisms. A GAG --> GAT polymorphism at codon 416 (frequencies = 0.41 and 0.59) results in Glu-->Asp, while a ACG-->AAG polymorphism at codon 420 (frequencies = 0.92 and 0.08) results in a Thr-->Lys. Sequencing of these codons in about 950 Pimas identified an association between the polymorphism at 420 and glucose and insulin responses to a 75g OGTT. Homozygotes for the ACG/ACG genotype had higher plasma insulin and glucose responses to a 75g OGTT (p<0.04 and p<0.006, respectively), higher plasma glucose responses to a mixed meal (p<0.002) and higher glucose levels during an intravenous glucose tolerance test (p<0.01) when compared to AAG/AAG homozgotes combined with the ACG/AAG heterozygotes.